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Research Summary

Signal transduction in the brain is a complex, highly regulated process. The transmission and regulation of nerve impulses between neurons are mediated by a number of proteins such as ion channels, G-protein coupled receptors, protein kinases, protein phosphatases, and neurotransmitter transporters. Importantly, many of these proteins are the target of potent psychoactive substances and antiepileptic drugs. Furthermore, their dysfunction has been implicated in the development of multiple debilitating neuropsychiatric and neurological diseases.

My lab is interested in elucidating the atomic mechanism by which these signaling proteins work, how disease-associated polymorphisms disrupt activity and regulation, and the mechanism by which therapeutic and illicit compounds exert their effects. We are currently focusing our efforts on neurotransmitter transporters. To achieve our objectives, we use a broad array of complementary biochemical and biophysical techniques, including X-ray crystallography, radioligand binding, and flux assays. Our ultimate goal is to help pave the road toward rational, structure-based drug design efforts and to shed light on the molecular underpinnings of disease-associated polymorphisms.

Extensive Research Description

Signal transduction in the human brain is a complex, highly regulated process. The transmission and regulation of nerve impulses among neurons are mediated by a number of proteins, including ion channels, G-protein coupled receptors, protein kinases, protein phosphatases, and neurotransmitter transporters, to name only a few. Significantly, many of these proteins are the target of potent psychoactive substances and antiepileptic drugs. Furthermore, their dysfunction has been implicated in the development of multiple debilitating neuropsychiatric and neurological diseases such as obsessive-compulsive disorder (OCD), autism, depression, schizophrenia, Parkinson’s disease, Tourette’s syndrome, and epilepsy.

Little is known about the molecular basis of these illnesses, but their underlying neural circuitry is gradually being revealed by a combination of functional neuroimaging, genome-wide association, transgenics, optogenetics, and neuropsychopharmacology. For instance, in OCD, an illness marked by intense intrusive thoughts and ritualistic behavior, hyperactivity in the circuit connecting the orbitofrontal cortex, cingulate gyrus, striatum, and caudate nucleus (the orbitofrontal corticostriatal circuit) has been correlated with symptom severity (Graybiel & Rauch, 2000). These brain regions receive extensive input from serotonergic and dopaminergic neurons, and both serotonin and dopamine have been implicated in the pathogenesis of OCD. Indeed, some of more effective treatments for OCD target the serotonin transporter (SERT) and include the tricyclic antidepressant (TCA) clomipramine and a few of the selective serotonin reuptake inhibitors (SSRIs). Although prescribed less frequently, atypical antipsychotics (dopamine D2 / serotonin 5HT2a receptor antagonists) are used as augmenting agents in treatment refractory cases.

My lab seeks to ascertain how signaling proteins in these neural circuits function at the atomic level, how disease-associated polymorphisms disrupt activity and how therapeutic and illicit compounds exert their effects. To achieve our objectives, we employ a broad range of complementary biochemical and biophysical tools such as X-ray crystallography, steady-state flux/binding kinetics, nanodisc technology, and hydrogen-deuterium exchange mass spectrometry (HDX-MS).

We are presently focusing our efforts on the plasma membrane neurotransmitter transporters for the biogenic amines serotonin (SERT) and dopamine (DAT). These molecular machines work by coupling preexisting sodium and chloride electrochemical gradients to the energetically unfavorable movement of the respective neurotransmitter from the synaptic cleft back into neuronal and glial cytoplasms. Because they function primarily after neurotransmitters have been released from the presynaptic neuron and activated postsynaptic receptors, these integral membrane proteins play a crucial role in terminating synaptic transmission and thus in shaping the duration and magnitude of synaptic signaling.

We are examining the substrate/ion specificity of these symporters and the dynamic conformational changes that occur during the transport cycle. We are also attempting to pinpoint antagonist binding sites and to elucidate the atomic mechanism by which psychoactive substances such as TCAs, SSRIs, cocaine, and amphetamine, modulate transport. Our ultimate goal is to help pave the road toward rational, structure-based drug design efforts and to shed light on the molecular underpinnings of disease-associated polymorphisms and drug resistance.

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Crystal structure of LeuT, a bacterial orthologue of the serotonin transporter, complexed with the tricyclic antidepressant clomipramine

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